CA2228196A1 - Process for preparing an optically active phenylglycidyl acid derivative - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/24—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
Abstract
The invention relates to a process for preparing an optically active trans-compound having formula (1), in which R represents a phenyl group, whether or not substituted, preferably p-methoxyphenyl, and A is derived from an optically active compound, in which an aldehyde having formula (2), in which R is as defined above, is, in the presence of a base, brought into contact with an optically active acetyl compound having formula (3), in which X represents a leaving group and in which A is derived from an amino alcohol, preferably a .beta.-amino alcohol having a rigid structure.
Particularly good results were obtained when use was made of a compound having formula (3), in which A is derived from an amino indanol compound having formula (4), in which R1 and R2 represent a (hetero)alkyl or (hetero)aryl group, whether or not substituted, having 1-10 C atoms, or R1 and R2 constitute an aromatic or aliphatic ring together with the N atom to which they are bound, in particular in which R1 and R2 each independently of one another represent methyl, ethyl, isopropyl, n-propyl, n-butyl, allyl, benzyl or tosyl.
Particularly good results were obtained when use was made of a compound having formula (3), in which A is derived from an amino indanol compound having formula (4), in which R1 and R2 represent a (hetero)alkyl or (hetero)aryl group, whether or not substituted, having 1-10 C atoms, or R1 and R2 constitute an aromatic or aliphatic ring together with the N atom to which they are bound, in particular in which R1 and R2 each independently of one another represent methyl, ethyl, isopropyl, n-propyl, n-butyl, allyl, benzyl or tosyl.
Description
PSV/ag (49641) PROCESS FOR PREPARING AN OPTICALLY ACTIVE
PHENYLGLYCIDYL ACID DERIVATIVE
The invention relates to a process for prepa~ing an optically active trans-phenylglycidic acid derivative having formula (1), O O
/ \ //
R - C - C - C (1) OA
in wh.ich R represents a phenyl group, whether or not subst.ituted, and A is derived from an optically active compound, in which an aldehyde having formula (2), //
R - C (2) H
in which R is as defined above, is, in the presence of a base, brought into contact with an optically active acetyl compound having formula (3), //
X - CH2 - C - OA (3) in which X represents a leaving group, characterized in that use is made of an optically active compound having formula (3) in which A is derived from an amino alcohol.
A similar process wherein an optically active trans phenylglycidic derivate with formula (1) is prepared in which A represents (-)-8-phenylmenthyl chloroacetate is known from EP-A-342904.
The process according to the invention provicles an alternative process wherein a high yield of the desired enantiomer and/or a high diastereomeric ratio can be obtained. Diastereoisomeric ratio means the (nnolar or weight) ratio between two diastereomeric isomers .
As the aldehyde use is made of an aldehyde having formula (2) in which R represents a phenyl group which may in one or more places be substituted with for example an alkyl group or an alkoxy group preferably having 1-20 C atoms in particular 1-5 C
atoms As the acetyl compound use is made of a compound having formula (3) in which X represents a leaving group and A a chiral group derived from an optically active amino alcohol (AOH). Groups that can be used as the leaving group are commonly known from the literature. Very suitable leaving groups are for examp]e halogenides in particular Cl- or Br~
sulphonates for example p-toluene or methane sulphonate. Amino alcohols from which A may be derived are for example (salts of) a ~-amino alcohol which preferably has a more or less rigid structure for example because of the amino alcohol containing a ring struct:ure. Particularly suitable examples of amino alcohols are substituted amino indanols having formula (4) ¦ O I ~ O - H (4) N
Rl R2 in wh:ich Rl and R2 represent a (hetero)alkyl, an alkenyl, a (hetero)aryl or an arylsulphonyl group, whether or not substituted, having 1-10 C atoms, or Rl and R, constitute an aromatic or aliphatic ring together with l:he N atom to which they are bound. The best resulls were obtained when use was made of a haloacetyl compolmd having formula (3), in which X represents Cl and A is derived from an enantiomerically pure (i.e.
having an enantiomeric excess (e.e.) ~ 95%, in partitular ~ 99%) cis-amino indanol having formula (4), in wh:ich Rl and R2 are each independently methyl, ethyl, isopropyl, n-propyl, n-butyl, allyl, benzyl or tosyl.
Preferably a non-nucleophilic base is used as the b~se, for example a hydride, in particular potassium hydride or sodium hydride; an alkyl lithium, more :in particular n-butyl lithium, or an alkoxide, preferably potassium t-butoxide. Preferably use is made of pol:assium t-butoxide.
As the solvent, use is made of for example chlor:inated hydrocarbons, aromatic hydrocarbons or ethers that are inert in the reaction system, for examp:Le dichloromethane, toluene, xylene or tetrahydrofuran (THF). Preferably use is made of toluene or dichloromethane.
The temperature at which the reaction is carried out is not particularly critical and preferably lies between -30 and 50~C, in particular between 10 and 40~C.
The molar ratio of the aldehyde and the acety:L compound is not critical either, and in practice prefe~ably lies between 1:2 and 2:1, in particular between 1:1.1 and 1.1:1, with a virtually equimolar ratio seeming optimum.
Preferably use is made of a slight excess of base relative to the acetyl compound, for example a base : acetyl compound molar ratio of between 1:1 and 1.5:1, preferably between 1:1 and 1.1:1. It will be clear that when A is derived from a salt of an optically active amino alcohol, for example the HCl salt, an extra equivalent of the base will need to be used.
Optically active phenylglycidyl acid derivatives obtained with the process according to the invent:ion can be used with particular advantage in the preparation of pharmaceuticals, in particular benzot;hiazepines, for example diltiazem and clenthiazem. The invention also relates to optically active phenylglycidyl acid derivatives having formula tl) and to the use thereof in the preparation of such pharmaceuticals.
In particular, the invention also relates to the new optically active compounds having formula (1) in whLch R represents a phenyl group, whether or not substLtuted, as defined above and A is derived from an optically active cis-amino ;n~nol (AOH) according to formula (4), in which R1 and R2 represent a (hetero)alkyl, an alkenyl, a (hetero)aryl or an arylsulphonyl group, whether or not substituted, having 1-10 C atoms, or R1 and R2 constitute an aromatic or aliphatic ring together with the N atom to which they are bound, R1 and R2 each independently preferably representing methyl, ethyl, isopropyl, n-propyl, n-butyl, allyl, benzyl or tosyl; and to the optically active acetyl compounds having formula (3), in which X
represents a leaving group and A is as defined above.
The optically active compounds having formula (1) can be used as such directly in the preparation of pharmaceuticals or they can first be converted into a corresponding phenylglycidyl ester, for example the methy], ethyl or t-butyl ester, for instance by reaction with a base and an alcohol e.g. an alkalimetal alkoxide with the desired ester corresponding alcohol as so]vent. These phenylglycidyl esters can in turn be converted into pharmaceuticals in a known manner, for examp:Le through coupling with an optionally substituted 2-amino thiophenol and cyclisation to a benzol:hiazepine. Such benzothiazepines are intermediates in the preparation of known pharmaceuticals, for example diltiazem and clenthiazem.
For the preparation of diltiazem use is made of for examp:Le the (2R,3S) compound having formula (1), in which R represents p-methoxyphenyl and A is derived from (lS, 2R)-amino ;n~nol, or a corresponding p-methoxyPhenylglycidyl ester obtained therefrom is firstbrought into contact with for example a 2-amino thiophenol, after which the reaction product obtained is subjected to a cyclisation reaction, optionally followed by an alkylation and acylation reaction.
The invention will now be further elucidated with reference to the examples, without being limited theret:o.
ExamP'Le I
(lS,2R)-1-(Diethylamino)-2-indanol A suspension of 15.09 grams (101 mmol) of (lS,2R)-1-amino-2-indanol, 33.72 grams (244 mmol) of potassium carbonate and 38.8 grams (249 mmol) of ethyl iodide in 100 ml of acetonitrile was refluxed for 3 hours After cooling, the solid matter was removed throuc~h filtration and the filtrate was evaporated. The residue was dissolved in 4N hydrochloric acid and was washed three times using dichloromethane. The water layer was made basic with the aid of a 50~ sodium hydroxide solution and was extracted with the aid of dichloromethane (3*25 ml). After drying (Na2SO4) and evaporation, the product was isolated as an oil. This oil WclS dissolved in diethyl ether and cooled, which caused the product to crystallise.
Yield 16.7 grams (81%) of a white solid substance.
MeltiIlg point: 60-61~C. [(X]20,, +1.1 (C=l, methanol). lH
NMR (200 MHz, CDCl3): 1.02 (t, 6H), 2.24-2.57 (2*m,4H), 2.65 (dd, lH), 3.20 (dd, lH), 4.22 (d, lH), 4.29 (q, lH), 4.7 (br s, lH) and 7.10-7.27 (m, 4H).l3C NMR
(50.3:L MHz, CDCl3): 13.63 (q), 41.42 (t), 45.60 (t), 66.97 (d), 68.95 (d), 125.44 (d), 126.17 (d), 126.45 5 (d), :L28.28 (d), 139.65(s) and 141.98 (s).
Examp:Le II
(lS,2R)-N-MethYl,N-i-PropYl-1-amino-2-indanol A solution of 4.0 grams of (lS,2R)-1-(i-10 propy:Lamino)-2-indanol (20.9 mmol), 30 ml of formic acid and 15 g of Formalin was refluxed for 24 hours.
After cooling, the reaction mixture was evaporated and disso:Lved in 50 ml of an aqueous 4N sodium hydroxide solut:Lon. The basic solution was extracted with the aid 15 of dichloromethane (2*50 ml). After drying (Na2SO4) and evaporation, the oil was chromatographed using silica gel 6t) (eluant: ethylacetate/petroleum ether (40-70) 3:1).
Yield 3.4 grams (79%) of a colourless oil. [~]2~D+8.6 20 (c=1, methanol). 1H NMR (200 MHz, CDCl3): 0.95 (d, 6H), 1.67 (s, 3H), 2.48 (dd, J=8.3 and 3.5 Hz, lH), 2.83 (septet, lH), 3.02 (dd, J=8.3 and 3.9 Hz, lH), 3.98-4.12 (m, 2H), 4.9 (br s, lH) and 6.94-7.08 (m, 4H).l3C
NMR (';0.31 MHz, CDCl3): 21.40 (q), 21.76 (q), 35.67 (q), 25 42.86 (t), 56.51 (d), 66.70 (d), 70.70 (d), 126.99 (d), 127.8:L (d), 128.40 (d), 129.66 (d), 140.63 (s) and 143.61 (s).
Example III
(lS,2R)-1-(Diethylamino)-2-indanYl chloroacetate 1.70 grams (17 mmol) of chloroacetyl chloride was added, drop by drop, in 5 minutes, to a solution of 2.65 grams (13 mmol) of (lS,2R)-1-(diethylamino)-2-indanol in 40 ml of dichloromethane at room temperature. The temperature increased to 30~C. The reaction was stirred for 15 hours at room temperature.
After evaporation of the solution, 4.15 grams (91%) of . CA 02228196 1998-01-29 HCl salt was obtained as a yellow foam.lH NMR (200 MHz, CDCl3~: 1.27 (t, 3H), 1.49 (t, 3H), 2.80 (septet, lH), 2.96-3.39 (m, 5H), 4.16 (d, J=7.8 Hz, lH), 4.41 (d, J=7.8 Hz, lH), 5.04 (br d, lH), 5.78 (q, lH), 7.15-7.37 (m, 3H), 7.55 (d, lH) and 11.5 (br s, lH).
The HCl salt can be quantitatively liberated to yield a colourless oil through extraction using a dichloromethane/5% K2CO3 solution in water. lH NMR (200 MHz, CDCl3): 0.97 (t, 6H), 2.40-2.71 (m, 4H), 2.93 (dd, 1.0 lH), 3.12 (dd, lH), 3.96 (s, 2H), 4.50 (d,lH), 5.56 (ddd, lH) and 7.15-7.30 (m, 4H).l3C NMR (50.31 MHz, CDCl3): 14.74 (q), 37.51 (t), 41.25 (t), 45.25 (t), 66.64 (d), 77.89 (d), 124.92 (d), 125.26 (d), 126.89 (d), 127.76 (d), 139.07 (s), 141.20 (s) and 167.03 (s).
Example IV
(lS,2R)-N-MethYl,N-i-ProPYl-l-amino-2-indanyl chlor~acetate 2.00 grams (17.5 mmol) of chloroacetyl chloride was added drop by drop, in 5 minutes, to a solution of 3.00 grams (14.6 mmol) of (lS,2R)-N-methyl,N-i-propyl-l-amino-2-; n~nol in 40 ml of dichl~romethane at room temperature. The temperature increased to 35~C. The reaction was stirred for 15 hours at ro~m temperature. This was followed by the addition of 50 ml of a 5% K2CO3 solution in water and extraction.
The basic water layer was once again extracted using 30 ml of dichloromethane. After the collected organic layers had been washed with water, dried using Na2SO4 and evaporated, 3.96 grams (85%) of product was isolated as a yellow oil. lH NMR (200 MHz, CDCl3): 1.05 (2*d, 6H), 2.09 (s, 3H), 2.96 (dd, J= 8.6 and 3.5 Hz +septet, 2H), 3.14 (dd, J= 8.6 and 3.5 Hz, lH), 3.99 (s, 2H), 4.47 (d, J=3,1 Hz, lH), 5.47 (dt, J=3,1 and 3.5 Hz, lH) and 7.10-7.25 (m, 4H).
3C NMR (50.31 MHz, CDCl3): 20.59 (q), 33.00 (q), 37.06 (t), 41.10 (t), 53.61 (d), 66.08 (d), 78.47 (d), 124.84 (d), 125.81 (d), 126.62 (d), 127.61 (d), 138.96 (s), 140.4~5 (s) and 166.85 (s).
ExamP:le V
(2R,3S)-3-(4-MethoxyPhenYl)oxirane-2-carboxYlic (lS,2R)-l-(diethylamino)-2-indanYl ester In 5-10 min., 0.95 grams (8.5 mmol) of potassium tert.-butoxide was added, in small portions, to a solution of 2.05 grams (7.3 mmol) of (lS,2R)-1-(diethylamino)-2-indanyl chloroacetate and 1.0 gram (7.3 mmol) of p-anisic aldehyde in 40 ml of toluene at 20 ~C. The temperature increased to 25 ~C. After 30 minutes' stirring the reaction was quenched using a diluted NaHCO3 solution in water. The organic layer was separated and washed with water, dried using Na2SO4and evaporated. Yield: 2.75 grams (90%) of a yellow oil.
This oil is a mixture of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic (lS,2R)-l-(diethylamino)-2-indanyl ester (diastereomeric ratio 89:11l and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert.-butyl ester (enantiomeric excess 80%).
H NMR (200 MHz, CDCl3): 1.02 (2*t, 6H), 2.48-2.78 (m,4H'l, 2.95-3.27 (m, 2H), 3.44 (d, J = 2.0 Hz) and 3.48 (d, J = 2.0 Hz, together lH for major and minor diastereomers, resp.), 3.80 (s, 3H), 4.02 (d, J = 2.0 Hz) and 4.07 (d, J = 2.0 Hz, together lH for minor and major diastereomers, resp.), 4.60 (d, lH), 5.62-5.75 (m, llI), 6.85 (d, 2H) and 7.15-7.38 (d+m, 6H). 13C NMR
(50.3:L MHz, CDCl3): 14.71 (q), 37.58 (t), 45.35 (t), 55.30 (q), 56.85 (d), 57.97 (d), 66.51 (d), 77.02 (d), 113.4!3 (d), 114.10 (d), 124.93 (d), 125.32 (d), 126.81 (d), :L27.12 (d), 127.27 (d), 127.74 (s), 139.16 (s), 160.18 (s) and 168.16 (s).
(2R,3',)-3-(4-Methoxyphenyl)oxirane-2-carboxylic tert.-butyl ester: 1H NMR (200 MHz, CDCl3): 1.43 (s, 9H), 3.33(d, lH), 3.73 (s, 3H), 3.89 (d, 3H), 6.81 (d, 2H) and 7.14 (d, 2H).
Examp:le VI
(2R,3S)-3-(4-MethoxYphenYl)oxirane-2-carboxylic (lS,2R)-1-(diethYlamino)-2-indanYl ester In 5-10 min., 3.50 grams (31 mmol) of potassium tert.-butoxide was added, in small portions, to a solution of 4.9 grams (12.5 mmol) of (lS,2R)-1-(dietllylamino)-2-indanyl chloroacetate HCl salt and 1.70 qrams (12.5 mmol) of p-anisic aldehyde in 50 ml of dichloromethane at 20 ~C. The temperature increased to 30 ~C. After 60 minutes' stirring the reaction was quenched using a 0.5M KH2PO4 solution in water. The organ:ic layer was separated and washed with water, dried using Na2SO4and evaporated. Yield: 5.10 grams (99%) of a brown oil (a mixture of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic (lS,2R)-l-(diethylamino)-2-indanyl ester (diastereomeric ratio 89:11'l and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert.-butyl ester (enantiomeric excess 75%)) Examp:Le VII
(2R,:3S)-3-(4-MethoxYphenYl)oxirane-2-carboxylic (lS,2R)-N-methyl,N-i-propyl-1-amino-2-indanyl ester In 5 min., 1.50 grams (13.4 mmol) of potas~;ium tert.-butoxide was added, in small portions, to a solution of 3.82 grams (12.0 mmol) of (lS,2R)-N-methy:L,N-i-propyl-l-amino-2-indanyl chloroacetate and 1.63 qrams (12.0 mmol) of p-anisic aldehyde in 50 ml of toluene at 20 ~C. The temperature increased to 33 ~C.
After 30 minutes' stirring the reaction was quenched with t:he aid of a lM NaHCO3 solution in water. The organLc layer was separated and washed with water, dried with the aid of Na2SO4and evaporated. Yield: 4.90 grams (98%) of a yellow oil (a 77:23 mixture of (2R,3',)-3-(4-methoxyphenyl)oxirane-2-carboxylic (lS,2R)-N-methyl,N-i-propyl-1-amino-2-indanyl ester (diast:ereomeric ratio 79:21) and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert.-butyl ester).
1H NME~ (200 MHz, CDCl3): 1.12 (2*d, 6H), 2.21 (s, 3H), 3.05-3.38 (m, 3H), 3.52 (d, J = 2.0 Hz, 0.95H), 3.56 (d, J = 2.0 Hz, 0.05H), 3.79 (s, 3H), 4.05 (d, J =2.0 Hz, lH), 4.60 (d, lH), 5.63 (m, lH), 6.91 (d, 2H) and 7.18-7.37 (d+m, 6H). l3C NMR (50.31 MHz, CDCl3): 20.53 (q), 20.80 (q), 33.35 (q), 37.17 (t), 53.34 (d), 55.23 (q), 56.76 (d), 57.83 (d), 66.22 (d), 78.16 (d), 114.02 (d), 124.89 (d), 125.81 (d), 126.62 (d), 127.02 (d), 127.56 (d), 127.91 (s), 139.06 (s), 141.0 (s), 160.08 (s) a;nd 167.90 (s).
ExamPle VIII
(2S,3S)-2,3-DihYdro-3-hYdroxY-2-(4-methoxYPhenyl)-l~5 benzothiazePin-4(5H)-on 2.0 grams (4.8 mmol) of the mixture of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic (lS,2R)-1-(diethylamino)-2-indanyl ester (diastereomeric ratio 89:11) and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert.-butyl ester (enantiomeric excess 80%) of Example V was dissolved in 20 ml of xylene + 1 ml of methanol. This solution was heated to 120 ~C and 600 mg (5.0 mmol) of 2-aminothiophenol was added drop by drop in 5 min. After 6 hours' heating at 120~C the solution was cooled to 20~C and 1.1 grams (6,0 mmol) of p-toluene sulphonic monohydrate was added. This was followed by 6 hours' heating at reflux temperature, during which 1-2 ml of a xylene/methanol mixture was removed through disti:Llation. After cooling, the brown solution was disso:Lved in dichloromethane and washed with a 5% Na2CO3 solut:ion in water and a 0.SM KH2PO4 solution in water.
After drying with the aid of Na2SO4 and evaporation, the chemically pure product was obtained after chromatography using silica gel (eluant: toluene/ethyl acetat:e 2:1). 85% enantiomeric excess (determined with the a:Ld of anisochrony in lH NMR, see C. Giordano et al.; ~r. Org. Chem. 1991, (59), 2270). The enantiomeric excess was increased to ~95% through one recrystallisation from toluene. White needles. Melting point: 200-202 ~C. [~]20D+109 (c=0.4, methanol). lH NMR
(200 MHz, CDCl3): 2.93 (d, lH), 3.71 (s, 3H), 4.41 (dd, lH), !,.02 (d, lH), 6.74 (d, 2H), 7.03-7.21 (m, 2H), 7.29-7.44 (d+m, 3H), 7.61 (d, lH) and 8.47 (br s, lH).
The (:LS,2R)-l-(diethylamino)-2-indanol was recovered from l:he 0.5M KH2PO4 extraction solution.
Examp:Le IX
(2R,3',)-3-(4-MethoxYPhenYl)oxirane-2-carboxYlic methyl ester A solution of 2.5 grams (6.3 mmol) of the react:Lon product of Example VII in 15 ml of 0.35M
sodiurn methoxide in methanol was stirred at room temperature for 1 hour. The solution was neutralised with t;he aid of 40 ml of a 0.5M KH2PO4 solution in water and WclS extracted with 2*30 ml chloroform. The chloroform solution was washed with 2*30 ml of a 0.5M
KH2PO4 solution in water. After drying (Na2SO4) and evaporation, 1.24 grams (95%) of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic methyl ester was obtained. Enantiomeric excess 55%. lH NMR (200 MHz, CDCl3): 3.47 (d, lH), 3.73 (s) and 3.76 (s, together 6H), ~L.Ol (d, lH), 6.85 (d, lH) and 7.18 (d, 2H). 13C
NMR ('iO.31 MHz, CDCl3): 52.00 (q), 54.78 (q), 55.99 (d), 57.40 (d), 113.59 (d), 126.17 (s), 126.66 (d), 159.73 (s) and 168.28 (s).
After neutralisation with the aid of a 50% sodium hydroxide solution in water and extraction with the aid of chloroform, 1.30 grams (100%) of (lS,2R)-N-methyl,N-i-propyl-l-amino-2-indanol was recovered from the acid water layers.
PHENYLGLYCIDYL ACID DERIVATIVE
The invention relates to a process for prepa~ing an optically active trans-phenylglycidic acid derivative having formula (1), O O
/ \ //
R - C - C - C (1) OA
in wh.ich R represents a phenyl group, whether or not subst.ituted, and A is derived from an optically active compound, in which an aldehyde having formula (2), //
R - C (2) H
in which R is as defined above, is, in the presence of a base, brought into contact with an optically active acetyl compound having formula (3), //
X - CH2 - C - OA (3) in which X represents a leaving group, characterized in that use is made of an optically active compound having formula (3) in which A is derived from an amino alcohol.
A similar process wherein an optically active trans phenylglycidic derivate with formula (1) is prepared in which A represents (-)-8-phenylmenthyl chloroacetate is known from EP-A-342904.
The process according to the invention provicles an alternative process wherein a high yield of the desired enantiomer and/or a high diastereomeric ratio can be obtained. Diastereoisomeric ratio means the (nnolar or weight) ratio between two diastereomeric isomers .
As the aldehyde use is made of an aldehyde having formula (2) in which R represents a phenyl group which may in one or more places be substituted with for example an alkyl group or an alkoxy group preferably having 1-20 C atoms in particular 1-5 C
atoms As the acetyl compound use is made of a compound having formula (3) in which X represents a leaving group and A a chiral group derived from an optically active amino alcohol (AOH). Groups that can be used as the leaving group are commonly known from the literature. Very suitable leaving groups are for examp]e halogenides in particular Cl- or Br~
sulphonates for example p-toluene or methane sulphonate. Amino alcohols from which A may be derived are for example (salts of) a ~-amino alcohol which preferably has a more or less rigid structure for example because of the amino alcohol containing a ring struct:ure. Particularly suitable examples of amino alcohols are substituted amino indanols having formula (4) ¦ O I ~ O - H (4) N
Rl R2 in wh:ich Rl and R2 represent a (hetero)alkyl, an alkenyl, a (hetero)aryl or an arylsulphonyl group, whether or not substituted, having 1-10 C atoms, or Rl and R, constitute an aromatic or aliphatic ring together with l:he N atom to which they are bound. The best resulls were obtained when use was made of a haloacetyl compolmd having formula (3), in which X represents Cl and A is derived from an enantiomerically pure (i.e.
having an enantiomeric excess (e.e.) ~ 95%, in partitular ~ 99%) cis-amino indanol having formula (4), in wh:ich Rl and R2 are each independently methyl, ethyl, isopropyl, n-propyl, n-butyl, allyl, benzyl or tosyl.
Preferably a non-nucleophilic base is used as the b~se, for example a hydride, in particular potassium hydride or sodium hydride; an alkyl lithium, more :in particular n-butyl lithium, or an alkoxide, preferably potassium t-butoxide. Preferably use is made of pol:assium t-butoxide.
As the solvent, use is made of for example chlor:inated hydrocarbons, aromatic hydrocarbons or ethers that are inert in the reaction system, for examp:Le dichloromethane, toluene, xylene or tetrahydrofuran (THF). Preferably use is made of toluene or dichloromethane.
The temperature at which the reaction is carried out is not particularly critical and preferably lies between -30 and 50~C, in particular between 10 and 40~C.
The molar ratio of the aldehyde and the acety:L compound is not critical either, and in practice prefe~ably lies between 1:2 and 2:1, in particular between 1:1.1 and 1.1:1, with a virtually equimolar ratio seeming optimum.
Preferably use is made of a slight excess of base relative to the acetyl compound, for example a base : acetyl compound molar ratio of between 1:1 and 1.5:1, preferably between 1:1 and 1.1:1. It will be clear that when A is derived from a salt of an optically active amino alcohol, for example the HCl salt, an extra equivalent of the base will need to be used.
Optically active phenylglycidyl acid derivatives obtained with the process according to the invent:ion can be used with particular advantage in the preparation of pharmaceuticals, in particular benzot;hiazepines, for example diltiazem and clenthiazem. The invention also relates to optically active phenylglycidyl acid derivatives having formula tl) and to the use thereof in the preparation of such pharmaceuticals.
In particular, the invention also relates to the new optically active compounds having formula (1) in whLch R represents a phenyl group, whether or not substLtuted, as defined above and A is derived from an optically active cis-amino ;n~nol (AOH) according to formula (4), in which R1 and R2 represent a (hetero)alkyl, an alkenyl, a (hetero)aryl or an arylsulphonyl group, whether or not substituted, having 1-10 C atoms, or R1 and R2 constitute an aromatic or aliphatic ring together with the N atom to which they are bound, R1 and R2 each independently preferably representing methyl, ethyl, isopropyl, n-propyl, n-butyl, allyl, benzyl or tosyl; and to the optically active acetyl compounds having formula (3), in which X
represents a leaving group and A is as defined above.
The optically active compounds having formula (1) can be used as such directly in the preparation of pharmaceuticals or they can first be converted into a corresponding phenylglycidyl ester, for example the methy], ethyl or t-butyl ester, for instance by reaction with a base and an alcohol e.g. an alkalimetal alkoxide with the desired ester corresponding alcohol as so]vent. These phenylglycidyl esters can in turn be converted into pharmaceuticals in a known manner, for examp:Le through coupling with an optionally substituted 2-amino thiophenol and cyclisation to a benzol:hiazepine. Such benzothiazepines are intermediates in the preparation of known pharmaceuticals, for example diltiazem and clenthiazem.
For the preparation of diltiazem use is made of for examp:Le the (2R,3S) compound having formula (1), in which R represents p-methoxyphenyl and A is derived from (lS, 2R)-amino ;n~nol, or a corresponding p-methoxyPhenylglycidyl ester obtained therefrom is firstbrought into contact with for example a 2-amino thiophenol, after which the reaction product obtained is subjected to a cyclisation reaction, optionally followed by an alkylation and acylation reaction.
The invention will now be further elucidated with reference to the examples, without being limited theret:o.
ExamP'Le I
(lS,2R)-1-(Diethylamino)-2-indanol A suspension of 15.09 grams (101 mmol) of (lS,2R)-1-amino-2-indanol, 33.72 grams (244 mmol) of potassium carbonate and 38.8 grams (249 mmol) of ethyl iodide in 100 ml of acetonitrile was refluxed for 3 hours After cooling, the solid matter was removed throuc~h filtration and the filtrate was evaporated. The residue was dissolved in 4N hydrochloric acid and was washed three times using dichloromethane. The water layer was made basic with the aid of a 50~ sodium hydroxide solution and was extracted with the aid of dichloromethane (3*25 ml). After drying (Na2SO4) and evaporation, the product was isolated as an oil. This oil WclS dissolved in diethyl ether and cooled, which caused the product to crystallise.
Yield 16.7 grams (81%) of a white solid substance.
MeltiIlg point: 60-61~C. [(X]20,, +1.1 (C=l, methanol). lH
NMR (200 MHz, CDCl3): 1.02 (t, 6H), 2.24-2.57 (2*m,4H), 2.65 (dd, lH), 3.20 (dd, lH), 4.22 (d, lH), 4.29 (q, lH), 4.7 (br s, lH) and 7.10-7.27 (m, 4H).l3C NMR
(50.3:L MHz, CDCl3): 13.63 (q), 41.42 (t), 45.60 (t), 66.97 (d), 68.95 (d), 125.44 (d), 126.17 (d), 126.45 5 (d), :L28.28 (d), 139.65(s) and 141.98 (s).
Examp:Le II
(lS,2R)-N-MethYl,N-i-PropYl-1-amino-2-indanol A solution of 4.0 grams of (lS,2R)-1-(i-10 propy:Lamino)-2-indanol (20.9 mmol), 30 ml of formic acid and 15 g of Formalin was refluxed for 24 hours.
After cooling, the reaction mixture was evaporated and disso:Lved in 50 ml of an aqueous 4N sodium hydroxide solut:Lon. The basic solution was extracted with the aid 15 of dichloromethane (2*50 ml). After drying (Na2SO4) and evaporation, the oil was chromatographed using silica gel 6t) (eluant: ethylacetate/petroleum ether (40-70) 3:1).
Yield 3.4 grams (79%) of a colourless oil. [~]2~D+8.6 20 (c=1, methanol). 1H NMR (200 MHz, CDCl3): 0.95 (d, 6H), 1.67 (s, 3H), 2.48 (dd, J=8.3 and 3.5 Hz, lH), 2.83 (septet, lH), 3.02 (dd, J=8.3 and 3.9 Hz, lH), 3.98-4.12 (m, 2H), 4.9 (br s, lH) and 6.94-7.08 (m, 4H).l3C
NMR (';0.31 MHz, CDCl3): 21.40 (q), 21.76 (q), 35.67 (q), 25 42.86 (t), 56.51 (d), 66.70 (d), 70.70 (d), 126.99 (d), 127.8:L (d), 128.40 (d), 129.66 (d), 140.63 (s) and 143.61 (s).
Example III
(lS,2R)-1-(Diethylamino)-2-indanYl chloroacetate 1.70 grams (17 mmol) of chloroacetyl chloride was added, drop by drop, in 5 minutes, to a solution of 2.65 grams (13 mmol) of (lS,2R)-1-(diethylamino)-2-indanol in 40 ml of dichloromethane at room temperature. The temperature increased to 30~C. The reaction was stirred for 15 hours at room temperature.
After evaporation of the solution, 4.15 grams (91%) of . CA 02228196 1998-01-29 HCl salt was obtained as a yellow foam.lH NMR (200 MHz, CDCl3~: 1.27 (t, 3H), 1.49 (t, 3H), 2.80 (septet, lH), 2.96-3.39 (m, 5H), 4.16 (d, J=7.8 Hz, lH), 4.41 (d, J=7.8 Hz, lH), 5.04 (br d, lH), 5.78 (q, lH), 7.15-7.37 (m, 3H), 7.55 (d, lH) and 11.5 (br s, lH).
The HCl salt can be quantitatively liberated to yield a colourless oil through extraction using a dichloromethane/5% K2CO3 solution in water. lH NMR (200 MHz, CDCl3): 0.97 (t, 6H), 2.40-2.71 (m, 4H), 2.93 (dd, 1.0 lH), 3.12 (dd, lH), 3.96 (s, 2H), 4.50 (d,lH), 5.56 (ddd, lH) and 7.15-7.30 (m, 4H).l3C NMR (50.31 MHz, CDCl3): 14.74 (q), 37.51 (t), 41.25 (t), 45.25 (t), 66.64 (d), 77.89 (d), 124.92 (d), 125.26 (d), 126.89 (d), 127.76 (d), 139.07 (s), 141.20 (s) and 167.03 (s).
Example IV
(lS,2R)-N-MethYl,N-i-ProPYl-l-amino-2-indanyl chlor~acetate 2.00 grams (17.5 mmol) of chloroacetyl chloride was added drop by drop, in 5 minutes, to a solution of 3.00 grams (14.6 mmol) of (lS,2R)-N-methyl,N-i-propyl-l-amino-2-; n~nol in 40 ml of dichl~romethane at room temperature. The temperature increased to 35~C. The reaction was stirred for 15 hours at ro~m temperature. This was followed by the addition of 50 ml of a 5% K2CO3 solution in water and extraction.
The basic water layer was once again extracted using 30 ml of dichloromethane. After the collected organic layers had been washed with water, dried using Na2SO4 and evaporated, 3.96 grams (85%) of product was isolated as a yellow oil. lH NMR (200 MHz, CDCl3): 1.05 (2*d, 6H), 2.09 (s, 3H), 2.96 (dd, J= 8.6 and 3.5 Hz +septet, 2H), 3.14 (dd, J= 8.6 and 3.5 Hz, lH), 3.99 (s, 2H), 4.47 (d, J=3,1 Hz, lH), 5.47 (dt, J=3,1 and 3.5 Hz, lH) and 7.10-7.25 (m, 4H).
3C NMR (50.31 MHz, CDCl3): 20.59 (q), 33.00 (q), 37.06 (t), 41.10 (t), 53.61 (d), 66.08 (d), 78.47 (d), 124.84 (d), 125.81 (d), 126.62 (d), 127.61 (d), 138.96 (s), 140.4~5 (s) and 166.85 (s).
ExamP:le V
(2R,3S)-3-(4-MethoxyPhenYl)oxirane-2-carboxYlic (lS,2R)-l-(diethylamino)-2-indanYl ester In 5-10 min., 0.95 grams (8.5 mmol) of potassium tert.-butoxide was added, in small portions, to a solution of 2.05 grams (7.3 mmol) of (lS,2R)-1-(diethylamino)-2-indanyl chloroacetate and 1.0 gram (7.3 mmol) of p-anisic aldehyde in 40 ml of toluene at 20 ~C. The temperature increased to 25 ~C. After 30 minutes' stirring the reaction was quenched using a diluted NaHCO3 solution in water. The organic layer was separated and washed with water, dried using Na2SO4and evaporated. Yield: 2.75 grams (90%) of a yellow oil.
This oil is a mixture of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic (lS,2R)-l-(diethylamino)-2-indanyl ester (diastereomeric ratio 89:11l and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert.-butyl ester (enantiomeric excess 80%).
H NMR (200 MHz, CDCl3): 1.02 (2*t, 6H), 2.48-2.78 (m,4H'l, 2.95-3.27 (m, 2H), 3.44 (d, J = 2.0 Hz) and 3.48 (d, J = 2.0 Hz, together lH for major and minor diastereomers, resp.), 3.80 (s, 3H), 4.02 (d, J = 2.0 Hz) and 4.07 (d, J = 2.0 Hz, together lH for minor and major diastereomers, resp.), 4.60 (d, lH), 5.62-5.75 (m, llI), 6.85 (d, 2H) and 7.15-7.38 (d+m, 6H). 13C NMR
(50.3:L MHz, CDCl3): 14.71 (q), 37.58 (t), 45.35 (t), 55.30 (q), 56.85 (d), 57.97 (d), 66.51 (d), 77.02 (d), 113.4!3 (d), 114.10 (d), 124.93 (d), 125.32 (d), 126.81 (d), :L27.12 (d), 127.27 (d), 127.74 (s), 139.16 (s), 160.18 (s) and 168.16 (s).
(2R,3',)-3-(4-Methoxyphenyl)oxirane-2-carboxylic tert.-butyl ester: 1H NMR (200 MHz, CDCl3): 1.43 (s, 9H), 3.33(d, lH), 3.73 (s, 3H), 3.89 (d, 3H), 6.81 (d, 2H) and 7.14 (d, 2H).
Examp:le VI
(2R,3S)-3-(4-MethoxYphenYl)oxirane-2-carboxylic (lS,2R)-1-(diethYlamino)-2-indanYl ester In 5-10 min., 3.50 grams (31 mmol) of potassium tert.-butoxide was added, in small portions, to a solution of 4.9 grams (12.5 mmol) of (lS,2R)-1-(dietllylamino)-2-indanyl chloroacetate HCl salt and 1.70 qrams (12.5 mmol) of p-anisic aldehyde in 50 ml of dichloromethane at 20 ~C. The temperature increased to 30 ~C. After 60 minutes' stirring the reaction was quenched using a 0.5M KH2PO4 solution in water. The organ:ic layer was separated and washed with water, dried using Na2SO4and evaporated. Yield: 5.10 grams (99%) of a brown oil (a mixture of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic (lS,2R)-l-(diethylamino)-2-indanyl ester (diastereomeric ratio 89:11'l and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert.-butyl ester (enantiomeric excess 75%)) Examp:Le VII
(2R,:3S)-3-(4-MethoxYphenYl)oxirane-2-carboxylic (lS,2R)-N-methyl,N-i-propyl-1-amino-2-indanyl ester In 5 min., 1.50 grams (13.4 mmol) of potas~;ium tert.-butoxide was added, in small portions, to a solution of 3.82 grams (12.0 mmol) of (lS,2R)-N-methy:L,N-i-propyl-l-amino-2-indanyl chloroacetate and 1.63 qrams (12.0 mmol) of p-anisic aldehyde in 50 ml of toluene at 20 ~C. The temperature increased to 33 ~C.
After 30 minutes' stirring the reaction was quenched with t:he aid of a lM NaHCO3 solution in water. The organLc layer was separated and washed with water, dried with the aid of Na2SO4and evaporated. Yield: 4.90 grams (98%) of a yellow oil (a 77:23 mixture of (2R,3',)-3-(4-methoxyphenyl)oxirane-2-carboxylic (lS,2R)-N-methyl,N-i-propyl-1-amino-2-indanyl ester (diast:ereomeric ratio 79:21) and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert.-butyl ester).
1H NME~ (200 MHz, CDCl3): 1.12 (2*d, 6H), 2.21 (s, 3H), 3.05-3.38 (m, 3H), 3.52 (d, J = 2.0 Hz, 0.95H), 3.56 (d, J = 2.0 Hz, 0.05H), 3.79 (s, 3H), 4.05 (d, J =2.0 Hz, lH), 4.60 (d, lH), 5.63 (m, lH), 6.91 (d, 2H) and 7.18-7.37 (d+m, 6H). l3C NMR (50.31 MHz, CDCl3): 20.53 (q), 20.80 (q), 33.35 (q), 37.17 (t), 53.34 (d), 55.23 (q), 56.76 (d), 57.83 (d), 66.22 (d), 78.16 (d), 114.02 (d), 124.89 (d), 125.81 (d), 126.62 (d), 127.02 (d), 127.56 (d), 127.91 (s), 139.06 (s), 141.0 (s), 160.08 (s) a;nd 167.90 (s).
ExamPle VIII
(2S,3S)-2,3-DihYdro-3-hYdroxY-2-(4-methoxYPhenyl)-l~5 benzothiazePin-4(5H)-on 2.0 grams (4.8 mmol) of the mixture of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic (lS,2R)-1-(diethylamino)-2-indanyl ester (diastereomeric ratio 89:11) and (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic tert.-butyl ester (enantiomeric excess 80%) of Example V was dissolved in 20 ml of xylene + 1 ml of methanol. This solution was heated to 120 ~C and 600 mg (5.0 mmol) of 2-aminothiophenol was added drop by drop in 5 min. After 6 hours' heating at 120~C the solution was cooled to 20~C and 1.1 grams (6,0 mmol) of p-toluene sulphonic monohydrate was added. This was followed by 6 hours' heating at reflux temperature, during which 1-2 ml of a xylene/methanol mixture was removed through disti:Llation. After cooling, the brown solution was disso:Lved in dichloromethane and washed with a 5% Na2CO3 solut:ion in water and a 0.SM KH2PO4 solution in water.
After drying with the aid of Na2SO4 and evaporation, the chemically pure product was obtained after chromatography using silica gel (eluant: toluene/ethyl acetat:e 2:1). 85% enantiomeric excess (determined with the a:Ld of anisochrony in lH NMR, see C. Giordano et al.; ~r. Org. Chem. 1991, (59), 2270). The enantiomeric excess was increased to ~95% through one recrystallisation from toluene. White needles. Melting point: 200-202 ~C. [~]20D+109 (c=0.4, methanol). lH NMR
(200 MHz, CDCl3): 2.93 (d, lH), 3.71 (s, 3H), 4.41 (dd, lH), !,.02 (d, lH), 6.74 (d, 2H), 7.03-7.21 (m, 2H), 7.29-7.44 (d+m, 3H), 7.61 (d, lH) and 8.47 (br s, lH).
The (:LS,2R)-l-(diethylamino)-2-indanol was recovered from l:he 0.5M KH2PO4 extraction solution.
Examp:Le IX
(2R,3',)-3-(4-MethoxYPhenYl)oxirane-2-carboxYlic methyl ester A solution of 2.5 grams (6.3 mmol) of the react:Lon product of Example VII in 15 ml of 0.35M
sodiurn methoxide in methanol was stirred at room temperature for 1 hour. The solution was neutralised with t;he aid of 40 ml of a 0.5M KH2PO4 solution in water and WclS extracted with 2*30 ml chloroform. The chloroform solution was washed with 2*30 ml of a 0.5M
KH2PO4 solution in water. After drying (Na2SO4) and evaporation, 1.24 grams (95%) of (2R,3S)-3-(4-methoxyphenyl)oxirane-2-carboxylic methyl ester was obtained. Enantiomeric excess 55%. lH NMR (200 MHz, CDCl3): 3.47 (d, lH), 3.73 (s) and 3.76 (s, together 6H), ~L.Ol (d, lH), 6.85 (d, lH) and 7.18 (d, 2H). 13C
NMR ('iO.31 MHz, CDCl3): 52.00 (q), 54.78 (q), 55.99 (d), 57.40 (d), 113.59 (d), 126.17 (s), 126.66 (d), 159.73 (s) and 168.28 (s).
After neutralisation with the aid of a 50% sodium hydroxide solution in water and extraction with the aid of chloroform, 1.30 grams (100%) of (lS,2R)-N-methyl,N-i-propyl-l-amino-2-indanol was recovered from the acid water layers.
Claims (16)
1. Process for preparing an optically active trans-phenylglycidic acid derivative having formula (1), in which R represents a phenyl group, whether or not substituted, and A is derived from an optically active compound, in which an aldehyde having formula (2), in which R is as defined above, is, in the presence of a base, brought into contact with an optically active acetyl compound having formula (3), in which X represents a leaving group, characterised in that use is made of an optically active compound having formula (3), in which A is derived from an amino alcohol.
2. Process according to Claim 1, in which R
represents a p-methoxyphenyl group.
represents a p-methoxyphenyl group.
3. Process according to Claim 1 or Claim 2, in which A is derived from an amino alcohol having a rigid structure .
4. Process according to Claim 3, in which A has a ring structure.
5. Process according to Claim 4, in which A is derived from an amino indanol compound having formula (4), in which R1 and R2 represent a (hetero)alkyl, an alkenyl or (hetero)aryl group, whether or not substituted, having 1-10 C atoms, or an arylsulphonyl group, or R1 and R2 constitute an aromatic or aliphatic ring together with the N
atoms to which they are bound.
atoms to which they are bound.
6. Process according to Claim 5, in which R1 and R2 each independently of one another represent an alkyl or an alkenyl group having 1-4 C-atoms, a benzyl or a tosyl group.
7. Process according to any one of Claims 1-6, in which potassium t-butoxide is used as the base.
8. Optically active compound having formula (3), in which X represents a leaving group, A is derived from an amino alcohol having formula (4) and R1 and R2 represent a (hetero)alkyl, an alkenyl or (hetero)aryl group, whether or not substituted, having 1-10 C atoms, or an arylsulphonyl group or R1 and R2 constitute an aromatic or aliphatic ring together with the N atom to which they are bound.
9. Optically active compound according to Claim 8, in which X represents Cl or Br.
10. Optically active compound having formula (1), in which R is as defined above and A is derived from an amino alcohol having formula (4), in which R1 and R2 represent a (hetero)alkyl, an alkenyl or (hetero)aryl group, whether or not substituted, having 1-10 C atoms, or a arylsulphonyl group, or R1 and R2 constitute an aromatic or aliphatic ring together with the N atom to which they are bound.
11. Optically active compound according to any one of Claims 8-10, in which R1 and R2 each independently of one another represent methyl, ethyl, n-propyl, isopropyl, n-butyl, allyl, benzyl or tosyl.
12. Process for preparing a phenylglycidyl ester in which first a compound having formula (1) is prepared according to any one of claims 1-7, after which this compound is subjected to a reaction with a base and an alcohol.
13. Process according to claim 12, in which the phenylglycidyl ester is subsequently reacted with aminothiophenol.
14. Process according to any one of Claims 1-7, in which process the compound having formula (1) is subsequently subjected to a reaction with an aminothiophenol.
15. Process according to claim 13 or 14, in which subsequently the product obtained is cyclisized and optionally subsequently alkylated and/or acylated.
16. Process according to Claim 15, in which diltiazem is obtained as the benzothiazepine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL1,005,338 | 1997-02-21 | ||
| NL1005338A NL1005338C2 (en) | 1997-02-21 | 1997-02-21 | Process for the preparation of an optically active phenylglycidyl acid derivative. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2228196A1 true CA2228196A1 (en) | 1998-08-21 |
Family
ID=19764467
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002228196A Abandoned CA2228196A1 (en) | 1997-02-21 | 1998-01-29 | Process for preparing an optically active phenylglycidyl acid derivative |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0860439B1 (en) |
| JP (1) | JPH10279572A (en) |
| CN (1) | CN1197070A (en) |
| AT (1) | ATE202094T1 (en) |
| CA (1) | CA2228196A1 (en) |
| DE (1) | DE69800900D1 (en) |
| HU (1) | HUP9800372A3 (en) |
| IL (1) | IL123391A0 (en) |
| NL (1) | NL1005338C2 (en) |
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|---|---|---|---|---|
| IT1302261B1 (en) | 1998-09-24 | 2000-09-05 | Zambon Spa | ENZYMATIC KINETIC RESOLUTION PROCESS OF 3-PHENYLGLYCIDATES FOR TRANSESTERIFICATION WITH AMINO-ALCOHOLS |
| DE602004014739D1 (en) * | 2003-03-12 | 2008-08-14 | Council Scient Ind Res | CHEMOENZYMATIC PROCESS FOR THE STEREOSELECTIVE MANUFACTURE OF OPTICALLY-ENRICHED PHENYL GLYCIDATE |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1329214C (en) * | 1988-05-18 | 1994-05-03 | James T. Palmer | 2-hydroxy-3-(4-methoxyphenyl)-3-(2- aminophenylthio)propionic acid, 8'-phenylmenthyl ester, especially for diltiazem |
-
1997
- 1997-02-21 NL NL1005338A patent/NL1005338C2/en not_active IP Right Cessation
-
1998
- 1998-01-29 CA CA002228196A patent/CA2228196A1/en not_active Abandoned
- 1998-02-16 DE DE69800900T patent/DE69800900D1/en not_active Expired - Lifetime
- 1998-02-16 EP EP98200484A patent/EP0860439B1/en not_active Expired - Lifetime
- 1998-02-16 AT AT98200484T patent/ATE202094T1/en active
- 1998-02-19 IL IL12339198A patent/IL123391A0/en unknown
- 1998-02-19 JP JP10076391A patent/JPH10279572A/en active Pending
- 1998-02-20 CN CN98107076A patent/CN1197070A/en active Pending
- 1998-02-20 HU HU9800372A patent/HUP9800372A3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0860439B1 (en) | 2001-06-13 |
| ATE202094T1 (en) | 2001-06-15 |
| DE69800900D1 (en) | 2001-07-19 |
| CN1197070A (en) | 1998-10-28 |
| EP0860439A1 (en) | 1998-08-26 |
| JPH10279572A (en) | 1998-10-20 |
| HUP9800372A2 (en) | 1999-09-28 |
| HUP9800372A3 (en) | 2001-02-28 |
| HU9800372D0 (en) | 1998-04-28 |
| IL123391A0 (en) | 1998-09-24 |
| NL1005338C2 (en) | 1998-08-24 |
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